The dual roles of chemokine (C-C motif) ligand 7 in tumors and inflammatory diseases

The structure of CCL7

The human CCL7 gene is located on chromosome 17q11.2-12 and comprises three exons and two introns. The first exon contains the 5′-UTR, an N-terminal signal sequence (23 amino acids), and the first two amino acids of the mature protein. The second exon encodes amino acids 3 to 42 of the mature protein, while the final exon encodes the C-terminal region and the 3′-UTR, which includes one or more AU-rich instability elements and a eukaryotic polyadenylation signal (Opdenakker et al., 1994; Weber et al., 1999). The transcription start site lies 16 base pairs downstream of the TATA box in the promoter region. Several regulatory elements modulate transcription upstream of the promoter: CRE and Ets-like elements notably suppress promoter activity (Opdenakker et al., 1994). Two enhancers are present—one spanning positions −172 to −110 and another located at position −37, only 21 base pairs upstream of the TATA box, known as the AP-1-like element (Murakami et al., 1997).

The receptor CCRs of CCL7

The CC chemokine receptors CCR1, CCR2, and CCR3 are widely recognized as the principal functional receptors of CCL7 (Griffith, Sokol & Luster, 2014; Palomino & Marti, 2015; Lee et al., 2016). Additionally, CCL7 has been reported to bind CCR5 (Jung et al., 2010) and CCR10 (Ford et al., 2019). These small chemokine receptors have a short N-terminal region and a short third intracellular loop. The C-terminal region is rich in serine and threonine residues, which are phosphorylation sites upon receptor activation. The extracellular loops and N-terminal region are essential for ligand binding (Murphy, 1996). The interaction of CCL7 with different receptors mediates distinct biological functions.

CCL7 is the ligand to CCR1, which is expressed in various cells such as monocytes, T cells, dendritic cells and neutrophils. Its protein consists of 355 amino acid residues and belongs to the peptide subfamily of the Class A G protein-coupled receptor family (Cheng & Jack, 2008). CCR1 signaling may contribute to inflammation by binding to CCL7 and facilitating macrophage infiltration (Wei et al., 2024). CCR2 is a widely studied and functional receptor expressed on the surface of monocytes/macrophages and lymphocytes, controlling monocyte mobilization, infiltration and their migration from the bloodstream to injured organs and damaged tissues. In colorectal cancer patients, elevated expression of both CCR2 and CCL7 has been observed, with overexpression of CCL7 significantly correlating with poorer survival outcomes (Kurzejamska et al., 2019). In the liver, damaged hepatocytes or hepatic stellate cells can promote macrophage infiltration, thus leading to inflammation and fibrosis by producing CCL7 (She et al., 2022). The CCL7-CCR3 axis regulates bone metabolism by promoting osteoblast differentiation and remodeling, offering potential therapeutic avenues for osteoporosis (Kim et al., 2024). Furthermore, the CCL7-CCR5 interaction is key in neuropsychiatric disorders and pain modulation (Szabo et al., 2002).

The expression profiles of chemokine receptors are highly complex and context-dependent, influenced by factors such as cell lineage, differentiation state, and microenvironmental cues—including chemokine concentration, presence of inflammatory cytokines, and hypoxia (Laurent et al., 2016).

Pro-tumor effects of CCL7

CCL7 promotes tumor growth, migration, and invasion. Autocrine signaling of CCL7 enhances tumor cell proliferation; in colorectal cancer (CRC) cells, lentiviral overexpression of CCL7 facilitates its binding to CCR3, activating the downstream Extracellular Regulated Protein Kinases (ERK)/ c-Jun N-terminal Kinases (JNK) signaling cascade of the mitogen-activated protein kinase (MAPK) pathway. This activation promotes epithelial-mesenchymal transition (EMT) and enhances the metastatic potential of CRC cells (Lee et al., 2016). Furthermore, CCL7 secreted by surrounding stromal cells contributes to tumor progression. In lung adenocarcinoma, CCL7 modulates immune responses within the tumor microenvironment, enhancing invasiveness (Parikh et al., 2018). Overexpression of SOX18—a critical indicator of survival and recurrence in gastric cancer—positively correlates with CCL7 levels, with CCL7 serving as a direct transcriptional target of SOX18. The CCL7-CCR1-SOX18 axis forms a positive feedback loop that continuously promotes gastric cancer invasion and metastasis (Chen et al., 2020b).

Anti-tumor effects of CCL7

As a chemokine, CCL7 recruits various leukocyte subsets, triggering immune responses. In early tumor development, fibroblasts can recruit and activate immune cells to generate extracellular matrix components that suppress tumor growth (LeBleu & Kalluri, 2018). In response to CCL7 activation, T lymphocytes enhance the production of granzyme and perforin, mediating tumor cell apoptosis. Moreover, CCL7 has been shown to inhibit tumor growth in a concentration-dependent manner. For instance, in the presence of CCL7, B78/H1 melanoma cells fail to establish tumors in murine models, and K1735 melanoma shows significantly reduced tumor formation and growth (Wetzel et al., 2007). Similarly, Infection of HeLa cells with hH1/MCP-3 induces high MCP-3 secretion, markedly suppressing tumor growth in recipient mice compared to controls (Hu et al., 2002).

In non-small cell lung cancer (NSCLC), CCL7 recruits conventional dendritic cell type 1 (cDC1), promotes CD8⁺ T cell expansion, and enhances the efficacy of anti-PD-1 therapy. CCL7 alone or in combination with PD-1 blockade significantly inhibits tumor growth (Zhang et al., 2020). In ovarian cancer, CCL7 deficiency accelerates tumor growth and reduces sensitivity to PD-1 inhibitors (Mollaoglu et al., 2024). Cancer cells may co-opt fibroblasts as fibrosis progresses, shifting their function from tumor suppression to tumor promotion (Kalluri, 2016; Hanahan & Weinberg, 2011). Thus, CCL7 holds promise as a novel molecular target for anti-tumor therapy (Table 1).

CCL7 and TME

As cancer research advances, increasing attention is being directed toward the TME, the dynamic ecosystem surrounding tumor cells, which includes vasculature, extracellular matrix (ECM), diverse signaling molecules, immune cells, fibroblasts, adipocytes, and other non-malignant components (Giraldo et al., 2019).

Tumor-associated macrophages

Tumor-associated macrophages (TAMs), predominantly composed of M2 macrophages with a minor M1 component, are implicated in tumor initiation, progression, angiogenesis, and metastasis (Mantovani et al., 2017; Xiang et al., 2021).

CCL7 plays a crucial regulatory role within the TME by modulating macrophage behavior. For T cells, TAMs foster angiogenesis and suppress T cell-mediated anti-tumor responses, thereby facilitating tumor progression (Yang & Zhang, 2017). In contrast, CCL7 downregulation enhances anti-tumor immunity via two key mechanisms: boosting CD8⁺ T cell infiltration and reversing T cell exhaustion (Zhang et al., 2025). Beyond this, elevated CCL7 levels create a favorable microenvironment for colorectal cancer hepatic metastasis (Mohr et al., 2017). In the liver, resident macrophages (Kupffer cells, KCs) modulate ECM remodeling to alter the hepatic tumor microenvironment (Kang, Gores & Shah, 2011; Rasool et al., 2013). Additionally, CCL7 secreted by immature monocytes or neutrophils enhances the migration and invasion of NSCLC cells (Zhang et al., 2020).

CCL7 and CAFs

CAFs are key players in tumor progression and represent a significant focus in oncology research (Zhang et al., 2023; Sahai et al., 2020). Typically derived from quiescent fibroblasts, CAFs drive tumor progression via CCL7-mediated intercellular crosstalk and downstream mechanisms (Sahai et al., 2020; Chen, McAndrews & Kalluri, 2021; Biffi & Tuveson, 2020).

First, CAFs could directly secret growth factors to promote tumor proliferation and metastasis. Activation of the nuclear factor kappa-B (NF-κB) pathway in CAFs significantly upregulates CCL7 secretion, promoting tumorigenesis. Conversely, suppression of CCL7 expression markedly impairs tumor growth (Jung et al., 2010). In hepatocellular carcinoma, elevated CCL7 expression activates the TGF-β/Smad2 signaling pathway to enhance tumor cell migration and invasion (Huang et al., 2025). Secondly, CAFs indirectly support tumor development through TME remodeling. CCL7 stimulation induces CAFs to secrete ECM-modulating factors, strengthen their interactions with tumor cells and facilitate tumor migration (Pestell et al., 2017). Collectively, these findings highlight the multifaceted role of CCL7 in modulating TME and driving tumor progression via diverse molecular pathways.

Targeting CCL7-CAFs axis for anti-tumor therapy

In terms of checkpoint inhibitors, in NSCLC, CCL7 recruits cDC1 to enhance CD8⁺ T cell expansion, thereby potentiating anti-PD-1 efficacy (Zhang et al., 2020). In contrast, CCL7 plays a role in maintaining sensitivity to PD-1 inhibitors in ovarian cancer. CCL7 deficiency reduces TAM infiltration and exacerbates anti-PD-1 resistance, while CCL7 expression reverses this phenotype (Mollaoglu et al., 2024). These findings support CCL7 as a predictive biomarker for checkpoint inhibitor response (Zhang et al., 2020; Mollaoglu et al., 2024). For CCL7-CAFs strategies, CAFs could directly secrete CCL7 through the NF-κB pathway (Jung et al., 2010), and CCL7 drives tumor progression via activation of the TGF-β/Smad2 (Huang et al., 2025) pathway. It also induces CAFs to secrete ECM-modulating factors such as collagens to create a microenvironment conducive to tumor metastasis (Pestell et al., 2017). Thus, targeting CCL7 could simultaneously inhibit both the direct pro-tumor effects and TME remodeling functions of CAFs. Therefore, targeting the key pathways that regulate CCL7 expression in CAFs, blocking their upstream activation signals via small-molecule inhibitors to reduce CCL7 production is feasible, such as NF-κB inhibitors (BAY 11-7082). Additionally, interfering with the interaction between CCL7 and its receptors (CCRs) using antibodies or antagonists, or inhibiting the activation of its downstream pathways, can disrupt the regulatory effects of CAF-derived CCL7 on tumor cells.

Inflammation-associated monocytes/macrophages

Monocytes are recruited to inflamed tissues, where they differentiate into macrophages capable of synthesizing a broad array of cytokines and growth factors, such as TGF-β and matrix metalloproteinases (MMPs), which are pivotal to host defense responses. Macrophages can be polarized into M1/M2 phenotypes with distinct functions. M1 macrophages are typically linked to pro-inflammatory responses with secretion of cytokines like TNF-α, IL-6 and IL-1β, while M2 macrophages are correlated with anti-inflammatory effects, secreting IL-4 and IL-10 (Varol, Mildner & Jung, 2015). However, macrophages exhibit high plasticity for M1/M2 polarization could dynamically shift in response to the surrounding microenvironment. A single macrophage population could switch between M1 and M2 phenotypes in response to different signals and diverse stimulation both in vivo and in vitro. Therefore, when we analyze how CCL7 affects macrophage polarization, it is necessary to consider carefully in the context of specific physiological scenarios, tissue types and species differences, instead of limiting our understanding of macrophages to the traditional M1/M2 classification framework.

The dual role of CCL7 in macrophage polarization is complex. On one hand, CCL7 could promote macrophage migration and exacerbate inflammatory processes. During liver injury, hepatocyte-derived CCL7 enhances inflammatory cell infiltration. CCL7 is highly increased in lesional psoriatic skin by TNF-a/IL-1b axis in mice (Brunner et al., 2015). In CCL7-deficient mice, both LPS- and MCD-induced liver injuries are mitigated, underscoring CCL7’s modulatory role in acute and chronic liver damage (Kong et al., 2021). In patients with inflammatory bowel disease, elevated CCL7-CCR2 signaling correlates strongly with macrophage infiltration, with heightened CCL7 expression driving the accumulation of pro-inflammatory macrophages in the intestinal tract (He et al., 2019).

On the other hand, neutrophils are more easily infiltrated into the infected skin to cause inflammation in CCL7-deficient mice, and improving the expression of CCL7 in vivo could alleviate inflammatory infections. In vitro, CCL7 can also directly antagonize neutrophil migration (Ford et al., 2019). CCL7 exerts anti-inflammatory and analgesic effects by binding to CCR receptors, facilitating the accumulation of monocytes. CCL7 deficiency stabilizes monocyte distribution between the bloodstream and bone marrow, thereby regulating their migration from bone marrow to blood and from blood to inflamed tissues, ultimately producing an anti-inflammatory effect (Tsou et al., 2007). Additionally, CCL7 plays a crucial role in conditions such as osteoarthritis, where its secretion alleviates joint pain in murine models (Pandey et al., 2024).

Notably, key controversies and knowledge gaps persist in current research. The molecular mechanisms underlying CCL7-mediated macrophage plasticity remain unclear. Most studies only get results using single cell lines or mouse models, which fail to simulate the complex intercellular interaction microenvironment in vivo. Furthermore, when CCL7 is used to stimulate cells, the concentration applied often exceeds physiological levels (Kong et al., 2021). These limitations mean that research conclusions cannot fully reflect the true mechanisms under physiological or pathological conditions.

In addition, the immune systems of humans and mice have structural and functional differences. Consequently, it is unreasonable to directly extend the role of CCL7 in human diseases from findings conducted on mouse models. Currently, there are few clinical reports on CCL7 and most only observe changes in CCL7 expression, lacking verification of underlying mechanisms (Choi et al., 2004; Kurzejamska et al., 2019).

Progression of fibrosis

Fibrosis, characterized by excessive extracellular matrix (ECM) deposition, is profoundly influenced by early-stage inflammation. Fibrotic processed are tightly associated with persistent early-stage inflammation. When the body gets injured, it sustains inflammatory responses that trigger the release of pro-inflammatory cytokines and growth factors, creating a pro-fibrotic microenvironment. These molecules not only enhance intercellular crosstalk between immune cells, stromal cells, and parenchymal cells but also activate the resident fibroblasts. A pro-fibrotic and anti-fibrotic balance governs the transition from acute inflammation to chronic fibrosis. Once this balance is disrupted, fibrosis progresses irreversibly in many cases.

As a proinflammatory chemokine, CCL7 is related to fibrosis progression in many tissues. In bleomycin-induced pulmonary fibrosis models, epithelial cell-derived CCL7 recruited macrophages by engaging CCR1/2/3 or CCR5/10, promoting their M1 polarization and driving fibrosis through activation of the NF-κB/STAT1 signaling pathway (Liu et al., 2023; Palomino & Marti, 2015; Zlotnik & Yoshie, 2012). In vitro, CCL7 directly stimulates dermal fibroblasts to express type I collagen (Ong et al., 2009; Ong et al., 2003). It activates TGF-β signaling, elevating the transcription of fibrogenic genes such as col1a2 and intensifying fibrotic progression. Furthermore, TGF-β stimulation enhances MCP-3 promoter activity within fibroblasts, suggesting a synergistic interplay that amplifies fibrogenic responses.

In tubulointerstitial fibrosis (TIF), marked by ECM accumulation within the interstitial space, leading to impaired renal function (Gonzalez et al., 2013; Klein et al., 2009). CCL7 exerts a dual role in the progression of TIF; it is detrimental in the early stage but beneficial in the late stage. In the early stage (Days 0–8), the fibrosis in CCL7-deficient mice was reduced, and infiltration of inflammatory cells and ECM production decreased. In contrast, during the late stage of obstruction (Days 10–14), TIF is exacerbated in CCL7-KO mice. Additionally, blocking the bradykinin B1 receptor to inhibit the expression of CCL7 can alleviate renal inflammation and fibrosis.

In addition, single-cell sequencing has revealed elevated CCL7 expression in the peripheral blood of patients with idiopathic pulmonary fibrosis (Unterman et al., 2024; Hasegawa, Takehara & Sato, 2006). Although CCL7 is strongly induced after acute kidney injury (AKI), CCL7 deficiency in mouse models fails to prevent the development of AKI and its progression to renal fibrosis (Casemayou et al., 2024). Therefore, CCL7 may not serve as a potential target for the prevention or treatment of AKI. Besides, the mechanisms underlying CCL7’s role in fibrosis also vary across different tissues. In conclusion, the switch of CCL7’s function in fibrosis depends on changes in the microenvironment.

The role in obesity and glucose metabolism

Obesity and type 2 diabetes are characterized by chronic low-grade inflammation, which intensifies as elevated cytokine and chemokine levels promote immune cell infiltration into metabolic organs such as the liver, pancreas, and brain (Gregor & Hotamisligil, 2011). Within adipose tissue, the accumulation of immune cells fosters chronic inflammation and favors the polarization of macrophages toward the pro-inflammatory M1 phenotype. These macrophages, in turn, secrete additional pro-inflammatory mediators, including TNF-α and IL-1β, further exacerbating systemic metabolic dysregulation (Liu et al., 2020).

CCL7 expression increases in obesity mice and humans. Elevated CCL7 levels have been documented in obese mice compared to lean counterparts (Tsuhako et al., 2020). In high-fat diet-induced obesity models, CCL7 enhances the aggregation of inflammatory factors and PKA1 phosphorylation through CCR5 activation, while MMP9-mediated microenvironmental alterations contribute to the promotion of drug resistance and cellular invasiveness (Bou Malhab et al., 2024). In obese individuals, CCL7 expression is markedly upregulated in omental and subcutaneous adipose tissues relative to lean controls (Huber et al., 2008).

CCL7 regulates β-cell death and contributes to islet damage. In the mouse model of type 1 DM, T cell exosomes stimulate CCL7 expression in β cells to attract immune cells and exacerbate β cell death (Guay et al., 2019). Furthermore, Macrophages are recruited in adipose tissue during obesity, CCL7 may be associated with adipocyte inflammation and insulin resistance in type 2 DM (Inouye et al., 2007). However, the precise mechanisms by which CCL7 regulates obesity and modulates lipid and glucose metabolism remain to be fully elucidated.

NF-κB signaling pathway

The nuclear factor NF-κB pathway is a classical signaling pathway in immunity and inflammation (Sun, 2017). CCL7 is a kind of proinflammatory cytokine that could activate the NF-κB signaling pathway (Lawrence, 2009). CCL7 inhibition reduced macrophage and neutrophil influx into the lung to relieve allergic airways disease in mice, and it was associated with active NF-κB p65 and p50 levels (Girkin et al., 2015). In RAW cells, CCL7 switched macrophages to M1 polarization and blocking the receptor CCR1 reduced the activation of the NF-κB pathway by inhibiting the phosphorylation of IKK, IκBα and p65 expression (Xu et al., 2025). In a pulmonary fibrosis model, CCL7 drives M1 macrophage polarization via the NF-κB/STAT1 pathway, promoting ECM deposition (Zlotnik & Yoshie, 2012).

MAPK signaling pathway

MAPK cascades are key signaling pathways that regulate cellular processes, including tumorigenesis, inflammation (Guo et al., 2020) and fibrosis. Among current articles, ERK prefers to be the common downstream of CCL7 in most diseases (Zhu et al., 2023; Chen et al., 2020a; Lee et al., 2016). CCL7 promoted human coronary artery smooth muscle cells proliferation by ERK1/2 and PI3K signaling pathway activation (Maddaluno et al., 2011). And CCL7 enhances colon cancer cell progression and EMT via CCL7-CCR3-ERK-JNK signaling (Lee et al., 2016).

Microenvironmental cues regulate signaling pathways

Some cytokines promote NF-κB, while hypoxia promotes MAPK. In inflammatory disease, TNF-α/IL-1β activates NF-κB, leading to high CCL7 expression in CX3CR1hi macrophages and forming a pro-inflammatory loop (He et al., 2019). In colorectal cancer liver metastases, hypoxia upregulates CCL7 via HIF-1α, and the pathway shifts to ERK dominance, enhancing tumor invasiveness and drug resistance (Chang et al., 2024; Mohr et al., 2017).

Different cell source affects pathway selection

In CAFs, CCL7 enhances tumor progression, and inhibiting NF-κB significantly reduces its pro-tumor effects (Jung et al., 2010). But hepatocytes upregulate CCL7 expression via NF-κB, recruiting inflammatory cells to exacerbate damage (Kong et al., 2021). Colorectal cancer cells could secrete CCL7 to activate the MAPK pathway to drive proliferation (Lee et al., 2016). In coronary artery smooth muscle cells, CCL7 synergistically promotes cell proliferation via the ERK and PI3K pathways (Chen et al., 2020a).

In total, NF-κB dominates in inflammation/fibrosis, while MAPK dominates in tumor metastasis. The differences between the two pathways are the molecular basis for the multifunctionality of CCL7.

CCL7 as a diagnostic and prognostic biomarker

CCL7 expression correlates with disease severity, progression, and treatment response across multiple pathological contexts, supporting its utility as a clinical biomarker. In ovarian cancer, CCL7 deficiency is associated with reduced sensitivity to PD-1 inhibitors, further validating CCL7 as a predictive biomarker for immunotherapy response (Mollaoglu et al., 2024). In TIF, urinary CCL7 levels are significantly higher in patients with early-stage renal injury and decrease with effective anti-fibrotic treatment, suggesting its potential as a non-invasive diagnostic marker for early TIF (Gonzalez et al., 2013). In type 1 diabetes (T1D), CCL7 expression in pancreatic islets is associated with β-cell death and T cell infiltration (Guay et al., 2019).

Therapeutic strategies targeting CCL7

Targeting CCL7 with multiple approaches has the potential to utilize its anti-disease functions. Evasins could bind chemokines and block their interaction with receptors. Evasin Class A1 and Class A3 exhibit high affinity for CC chemokines, including CCL7. Small-molecule inhibitors or neutralizing antibodies or gene knockout approaches targeting CCL7’s receptors (CCR1, CCR2, CCR3) inhibit further progression of the disease in preclinical studies (Lee et al., 2016; Schmall Al-Tamari et al., 2015; Xu et al., 2025). Combining CCL7-targeted agents with existing treatments enhances therapeutic efficacy. In NSCLC, CCL7 overexpression synergizes with anti-PD-1 therapy by recruiting cDC1 and expanding CD8⁺ T cells (Zhang et al., 2020).